Combining Sibutramine With Diet Modification For The Management Of Metabolic Syndrome In SD Rats

Objective:The current study aimed to assess the efficacy of sibutramine on metabolic syndrome?MetS?in SD rats and effect of diet structure on sibutramine,and to further provide a basis for the development of sibutramine analogues for the treatment of metabolic syndrome and the effect of diet structure on drug action during treatment.Methods:In this study,the male Sprague Dawley rats were fed with high fat chow and tap water for10 weeks,and fed with high fat chow and fructose solution for additional 3 weeks to establish MetS model.MetS rats were treated with sibutramine(4 mg·kg^-1·day^-1,Sib),dietary modification?standard chow and tap water,SCW;standard chow and high fructose water,SCFr?or combination therapy?SCW+Sib,SCFr+Sib?for 3 weeks after grouping.Body weight and food intake were monitored daily during the treatment.Animals underwent oral glucose tolerance test?OGTT?2 days prior to sacrifice.Blood was collected immediately before death.Animal perirenal,epididymal and omental fat pads were removed and weighed.Animal livers,hearts and kidneys were stored for subsequent measurement.Histopathological methods were used to observe changes in the liver,heart and kidneys.Biochemical methods were used to determine serum and hepatic lipid profile?TG,TC,HDL-C,LDL-C and NEFA?,and serum biochemical criterions?TBil,AST,ALT,ASP,Crea and Urea?.Serum insulin level was measured by ELISA assay.Western blot analysis was performed to determine hepatic expression of markers related to fat metabolism.Results:1.SD rats loaded by HFFr presented central obesity,impaired glucose tolerance,lipid metabolism disorders,and pathological changes in liver,heart and kidney when compared with normal rats.2.Although SCW significantly lowered omental fat pad and serum TG,SCW resulted in a notable increase in food intake after the second day of treatment and a significant reduction in ISI when compared with model?P<0.05?.SCFr alone significantly lowered final body weight,body fat pad,post-OGTT glucose AUC,serum TG and hepatic TG compared with model?P<0.05?.Sibutramine treatment alone markedly reduced food intake from D1 to D6,final body weight,body fat pad,post-OGTT glucose AUC,serum TG and hepatic TG when compared with model?P<0.05?.SCW significantly improved the effect of sibutramine on NEFA?P<0.05?.SCFr significantly improved the effect of sibutramine on average weekly weight changes,FBG,ISI and NEFA?P<0.05?.Western blotting showed that Sib and SCFr+Sib inhibited the expression of the protein related to lipid synthesis in the liver.While SCW+Sib promote the expression of the protein related to lipid synthesis in the liver.Each treatment resulted in a degree of pathological change in the heart,liver and kidney.Conclusions:1.Sibutramine can significantly improve abdominal obesity in rats with metabolic syndrome,while it has limited effect on impaired glucose tolerance and lipid metabolism disorders.2.SCFr and sibutramine have synergistic effects on improving abdominal obesity,impaired glucose tolerance and lipid metabolism disorders in rats with metabolic syndrome.But SCFr+Sib also presented certain toxicity on the heart and kidney in rats.